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Open Access Research article

Investigation of 95 variants identified in a genome-wide study for association with mortality after acute coronary syndrome

Thomas M Morgan1*, John A House2, Sharon Cresci3, Philip Jones2, Hooman Allayee4, Stanley L Hazen5, Yesha Patel4, Riyaz S Patel67, Danny J Eapen6, Salina P Waddy8, Arshed A Quyyumi6, Marcus E Kleber9, Winfried März10, Bernhard R Winkelmann11, Bernhard O Boehm12, Harlan M Krumholz4 and John A Spertus2

Author Affiliations

1 Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN USA

2 Saint Luke's Mid America Heart Institute and University of Missouri-Kansas City, Kansas City, MO USA

3 Department of Internal Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO USA

4 Department of Preventive Medicine, USC Keck School of Medicine, Los Angeles, CA USA

5 Center for Cardiovascular Diagnostics and Prevention, Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

6 Emory University School of Medicine, Atlanta, GA, USA

7 Cardiff University, Cardiff, Wales, UK

8 NINDS/NIH, Bethesda, MD, USA

9 LURIC non profit LLC, Freiburg im Breisgau, Germany, and Mannheim Institute of Public Health, Medical Faculty Mannheim, University of Heidelberg, Germany

10 synlab Services GmbH, Mannheim, and Mannheim Institute of Public Health, Medical Faculty Mannheim, University of Heidelberg, Germany, and Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Austria

11 Cardiology Group Sachenhausen, Frankfurt Sachsenhausen, Germany

12 Division of Endocrinology, Diabetes and Metabolism, Graduate School of Molecular Diabetology and Endocrinology, Ulm University, Germany; 13Robert Wood Johnson Clinical Scholars Program and Department of Internal Medicine, Yale University School of Medicine, New Haven, CT USA

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BMC Medical Genetics 2011, 12:127  doi:10.1186/1471-2350-12-127

Published: 29 September 2011

Abstract

Background

Genome-wide association studies (GWAS) have identified new candidate genes for the occurrence of acute coronary syndrome (ACS), but possible effects of such genes on survival following ACS have yet to be investigated.

Methods

We examined 95 polymorphisms in 69 distinct gene regions identified in a GWAS for premature myocardial infarction for their association with post-ACS mortality among 811 whites recruited from university-affiliated hospitals in Kansas City, Missouri. We then sought replication of a positive genetic association in a large, racially diverse cohort of myocardial infarction patients (N = 2284) using Kaplan-Meier survival analyses and Cox regression to adjust for relevant covariates. Finally, we investigated the apparent association further in 6086 additional coronary artery disease patients.

Results

After Cox adjustment for other ACS risk factors, of 95 SNPs tested in 811 whites only the association with the rs6922269 in MTHFD1L was statistically significant, with a 2.6-fold mortality hazard (P = 0.007). The recessive A/A genotype was of borderline significance in an age- and race-adjusted analysis of the entire combined cohort (N = 3095; P = 0.052), but this finding was not confirmed in independent cohorts (N = 6086).

Conclusions

We found no support for the hypothesis that the GWAS-identified variants in this study substantially alter the probability of post-ACS survival. Large-scale, collaborative, genome-wide studies may be required in order to detect genetic variants that are robustly associated with survival in patients with coronary artery disease.